Interpreting the Genome

Interpreting the Genome

But the greatest challenge in the next phase of human genomics is likely to be interpreting the meaning of the seemingly endless array of variations that will be uncovered. Individual genetic changes occur by chance, and some are harmless. Others happen to be dangerous, disrupting some vital cellular process and raising the risk of disease. And some may even be beneficial–enhancing the breakdown of toxins, for example, and thus protecting against certain ailments. But it’s often impossible to tell which class a variation falls into just by looking at it. And as new technologies allow scientists to sequence the genomes of large numbers of people, the list of known variants will quickly grow. “This information is going to be thorny and problematic in terms of interpretation,” says James Evans, a professor of genetics and medicine at the University of North Carolina at Chapel Hill. “We all have mutations and alterations that we simply don’t understand. As usual, the technology will be ahead of our ­ability to use it.”

The complexity of the new genomic information may also be an obstacle to the personalized medicine that gene sequencing was supposed to usher in. Researchers have hoped to create tests that predict an individual’s risk for a specific disease or reveal which drug is likely to work best for him or her. But genetic tests that detect newly discovered variations won’t be very useful until scientists can figure out what those variations mean. And if many common diseases are caused by rare variants, the task will be enormous. “Understanding risk based on rare variants is going to take us years,” says Dietrich Stephan, founder and chief science officer of Navigenics, a personal-genomics startup.

Some scientists think that the real value of genomics may not lie in personalized medicine at all. Where it will really pay off, they say, will be in deepening our understanding of disease and helping researchers discover new targets for drugs. “The primary value of genetic mapping is not risk prediction, but providing novel insights about mechanisms of disease,” wrote David Altshuler, a physician and geneticist at the Broad Institute in Cambridge, MA, in a recent article published in the journal ­Science. In fact, Altshuler points out, identifying even rare genetic changes can end up helping a large number of patients. For example, studies of an inherited form of high cholesterol found in less than 0.2 percent of the population led to the discovery of the low-density lipoprotein (LDL) receptor, which helps to remove excess cholesterol from the bloodstream. That in turn led to the development of the blockbuster drugs known as statins, cholesterol-lowering medications that trigger an increase in the number of LDL receptors on the surfaces of liver cells.

No one knows when the next blockbuster will arrive. Making predictions about the benefits of genomics has become as thankless as trying to predicting disease risk itself. And the easier it gets to sequence a genome, the harder it becomes to make sense of the complexity the sequences reveal. As ­Collins puts it, “The Human Genome Project was perhaps a simple undertaking compared to what we face next.”